Citations 2
Genome-Wide Association Study of Peripheral Artery Disease
Zuydam, Natalie R. van , Stiby, Alexander, Abdalla, Moustafa , Austin, Erin , McLachlan, Stela , Vlachopoulou, Efthymia, Ahlqvist, Emma , Liao, Chen Di , Sandholm, Niina , Robertson, Neil R., Rayner, Nigel W. , Lindholm, Eero , Sinisalo, Juha , Kallio, Milla , Weiss, Emily , Price, Jackie F. , Paterson, Andrew D. , Klein, Barbara E.K. , Palmer, Colin N.A. , Groop, Per‐Henrik , Groop, Leif , Morris, Andrew P. , Hopewell, Jemma C. , Colhoun, Helen M. , Grétarsdóttir, Sólveig , Þorsteinsdóttir, Unnur , Stefánsson, Kāri , Michael, Mark , Kanninen, Timo, Patrono, Carlo, Nuutila, Pirjo , McKeague, Paul, Steckel-Hamann, Birgit, Gan, Li‐Ming , Nogoceke, Everson, Jablonka, Bernd, Brosnan, Mary-Julia, van Zuydam, Natalie R , Ahlqvist, Emma , Di Liao, Chen , Sandholm, Niina , Forsblom, Carol , Rayner, N William , Lindholm, Eero , Sinisalo, Juha , Perola, Markus , Kallio, Milla , Weiss, Emily , Paterson, Andrew , Salomaa, Veikko , Palmer, Colin N A , McCarthy, Mark I , de Andrade, Mariza , Hopewell, Jemma C , Colhoun, Helen M , Kullo, Iftikhar J , Dahlström, Emma H. , Mahajan, Anubha , McCarthy, Mark I. , Andrade, Mariza de , Kullo, Iftikhar J. , Þorleifsson, Guðmar , Mark, Michael, Thorand, Barbara , Remuzzi, Giuseppe , Dunger, David B. , Shore, Angela C. , Smith, Ulf , Ylä-Herttuala, Seppo , Cobelli, Claudio , Bellazzi, Riccardo , Ferrannini, Ele , Patrono, Carlo, Tortoli, Piero
Circulation: Genomic and Precision Medicine | October 4, 2021 | Volume: 14 | Issue: 5 | Pages: No page available
Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant ( P association ≤5×10 −8 ) associations with PAD in 449 548 (N cases =12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1 ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], P diabetes =2.5×10 −9 , P interactionwithdiabetes =5.3×10 −7 ). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], P smokers =9.3×10 −10 , P interactionwithsmoking =3.9×10 −5 ). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
Targeted Sequencing Study to Uncover Shared Genetic Susceptibility Between Peripheral Artery Disease and Coronary Heart Disease—Brief Report
Safarova, Maya , Fan, Xiao , Austin, Erin , Zuydam, Natalie Van, Hopewell, Jemma C. , Schaid, Daniel J. , Safarova, Maya S, Austin, Erin E, Hopewell, Jemma C , Kullo, Iftikhar J.
Arteriosclerosis, Thrombosis, and Vascular Biology | April 11, 2019 | Volume: 39 | Issue: 6 | Pages: 1227-1233
Objective— It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results— Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO , and ZEB2 to be associated with PAD ( P <4.5×10 −5 ). At the gene level, the strongest associations were for LPL and SH2B3 . Conclusions— Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.